Microcapsules have many applications, such as in the manufacture of pharmaceuticals, herbicides, foods, cosmetics, pesticides, paints, adhesives, and many other chemical products. Microcapsules are especially useful where it is desired to provide a controlled release of the substance being encapsulated.
Various processes for forming microcapsules are described in the references: Vandegaer, “Microencapsulation Processes and Applications”, Plenum Press, New York, 1974, M. Gutcho, “Microcapsules and other Capsules”, Chemical Technology Review, No. 135, Noyles Data Service, Park Ridge, N.J. 1979, and the Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition (1981), volume 15. The above-mentioned references describe several liquid-phase methods of encapsulation. These methods include coacervation, thermal coacervation, complex coacervation, interfacial polymerization, and others. In the process of coacervation, the core and shell materials are mixed together in a liquid medium. When the core and shell materials have been agitated for a sufficient period of time, portions of the core material become coated with shell material, thus forming capsules within the liquid medium. The size of these capsules is controlled by the speed and design of the mixing element within the vessel. A further chemical treatment process adjusts the thickness of the shell material.
Microcapsules used in industry must be capable of withstanding large shear forces, or other stressful conditions, when the capsules are added to a host material. Suitable host materials could be paints, plastics, foam products, building materials, paper products and others. Each host material requires varying conditions of heat and stress to produce the final product, and the capsules must have suitable physical properties to enable the capsules to be used during the manufacture of the final product. Capsules used in industry must generally be very small.
There are special problems in the development of sustained release compositions, and particularly zero order release compositions, of environmentally sensitive materials or biologically active macromolecules due to the susceptibility to chemical and structural alteration or reaction upon mixing with excipients, upon processing and upon storage. These problems are understood by those skilled in the art of pharmaceutical formulation and can be categorized as problems of chemical stability. Inadequate chemical stability of compositions resulting from irreversible alteration of the structure of the core and/or interactions with the excipients can result in compositions that are either inactive or do not provide the desired function.
Another category of problems for pharmaceutical formulations is physical stability. One obvious example is attrition of tablets or implants during processing, packaging, or storage. Another example is a physical separation of a cream, paste or gel into component parts, which can lead to a heterogeneous distribution of active ingredient as well as alteration of the consistency. The consequence of such physical deterioration of the formulation can be loss of the desired ease of use characteristics and an unpredictable dosing to the patient. Less obvious physical changes in a pharmaceutical formulation include various alterations to the crystalline or microscopic structure of the excipients. These types of changes can lead to marked alterations in the release of active agents. It should be clear that changes in the physical stability of pharmaceutical dosage forms whether they are for oral or parenteral administration would be most problematic for sustained release preparations. It is the sine qua non of commercially viable sustained release pharmaceutical dosage forms that they have maintained release characteristics across production lots and after relatively long periods of time in storage. Physical stability of the pharmaceutical dosage form is intended to describe both constancy of the handling characteristics such as hardness, flowability, or viscosity, and constancy of pharmacological performance.
The present invention provides a specific dual mechanism release profile microcapsule and a method for its preparation.
Reported Developments
Microencapsulation technology has long been used for the controlled delivery of pharmaceuticals. As early as 1964 aspirin was encapsulated in ethylcellulose (U.S. Pat. No. 3,155,590) with improvements made to the basic process (U.S. Pat. No. 3,341,416). Microencapsulation has also been used to deliver potassium salts to humans (U.S. Pat. No. 4,259,315).
Other drugs have also been microencapsulated using a variety of methods. For example, U.S. Pat. No. 4,938,967 discloses microcapsules with a higher than usual density by including a weighting agent, such as barium sulphate, to increase the residence time in the stomach. U.S. Pat. No. 4,574,080 discloses a controlled release formulation that contains additional particles of the active substance adhered to the surface of the coating. U.S. Pat. No. 4,606,940 discloses a process for encapsulation by dissolving the compound to be encapsulated in a solvent, mixing the solution with a solution of encapsulating material and electrolyte, and gelling the encapsulating material.
One of the primary reasons for encapsulating a drug is to slow the release of the drug into the body. Thus, a controlled release microencapsulated formula may be substituted for several non-microencapsulated doses. The release rate of the drug is typically controlled primarily through the thickness of the coating. Typically the release pattern is first order in which the rate decreases exponentially with time until the drug is exhausted (Kirk-Othmer, Encyclopedia of Chemical Technology, p. 485, 1981). This release pattern is due to the concentration difference between that inside and that outside the capsule which difference decreases continuously during dissolution.
Exemplary sustained release microcapsules include those described in the following patents:
U.S. Pat. No. 4,837,381 discloses a microsphere composition of fat or wax or mixture thereof and a biologically active protein, peptide or polypeptide suitable for parenteral administration. The patent discloses the utility of the compositions for slow release of a protein, peptide or polypeptide in a parenteral administration, and discloses methods for increasing and maintaining increased levels of growth hormone in the blood of treated animals for extended periods of time and thereby increasing weight gains in animals and increasing milk production of lactating animals by the administration of compositions of the invention.
U.S. Pat. No. 5,213,810 discloses water insoluble fat or wax microspheres containing biologically active protein, peptides or polypeptides wherein the fat or wax shell includes an oil, semi-soft fat or fatty acid derivative disclosed as stabilizing the microsphere by accelerating the formation of the beta crystal form of the fat or wax subsequent to spray atomization of the mixture.
However, often a zero order, constant-release rate is preferred in which case the microcapsules deliver a fixed amount of drug per unit time over the period of their effectiveness. Zero-order release core delivery systems provide for the core to be released at a uniform rate independent of the core concentration (in the dosage form) during the period of release. Such an ideal core delivery system can produce uniform core concentration levels for a prolonged period of time. In a pharmaceutical system, the zero-order delivery system is capable of providing maximum therapeutic value while minimizing the side effects. It-can also reduce the dosing frequency to once in twelve hours or once in twenty-four hours, thus improving the dosage compliance on the part of subjects.
Except for reservoir devices, zero-order release of microcapsules has rarely been reported. Zero-order release with reservoir devices is obtained until no excess drug is left in contact with a saturated drug solution in the reservoir. For example, in the 1986 paper, M. Donbrow, School of Pharmacy, Jerusalem, Israel presented at the 13th International Symposium on Controlled-Release of Bioactive Materials, Aug. 3–6, 1986—Norfolk, Va., the author states “Microcapsule release literature includes many unvalidated reports of exponential release, also some matrix release (M=kt.1/2 or Higuchi kinetics), and dissolution rate-limiting release (m. 1/3 alpha. t), but very rarely zero-order release.”
A pertinent recent purported example of a zero order release microcapsule composition is reported in U.S. Pat. No. 5,252,337, which discloses an ethylcellulose microcapsulated formulation of a calcium channel blocker with a controlled release from about 8 to about 24 hours, more narrowly from about 12 to about 16 hours. The '337 patent discloses that the ethylcellulose microencapsulated formulation of a calcium channel blocker exhibits an approximately zero order release rate.
U.S. Pat. No. 3,845,770 describes an osmotic device for the zero-order release of an active agent. The osmotic device disclosed in this patent consists of an active agent enclosed in a semi-permeable wall. The semi-permeable wall is permeable to the passage of an external fluid but is substantially impermeable to the passage of the active agent in solution with the external fluid. An osmotic passageway is provided through the wall to deliver the solution of the active agent in the external fluid to the environment. The patent thus teaches the use of osmotic delivery of the active agent solution through a specially constructed passageway instead of delivery via diffusion through a membrane.
U.S. Pat. No. 4,327,725 describes how to enhance the delivery kinetics of the basic osmotic pump via use of a hydrogel layer inside the semi-permeable membrane. The structure of the device consists of an active agent enclosed in a hydrogel layer that is enclosed by a semi-permeable membrane. The semi-permeable membrane allows diffusion of external fluid to inside but does not allow the diffusion of the solution of active agent in the external fluid to the surrounding environment. The hydrogel swells with absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then delivered to the surrounding media through a single specially constructed passageway through the hydrogel layer and the membrane. It is claimed that the variation described in U.S. Pat. No. 4,327,725 is particularly useful in case of drugs that are insoluble in the external fluid. The osmotic passageway in the device described in this patent is created by drilling a hole through the semi-permeable wall to connect the active agent compartment with the exterior of the device. A laser-machine is utilized to drill precise holes. This procedure is cumbersome and requires a considerable development effort to tailor the delivery system to each individual drug or active agent.
U.S. Pat. No. 4,891,223 discloses a bioactive composition having a controlled, sustained release delivery pattern when contacted with a suitable surrounding media. The composition comprises a pharmaceutically, insecticidally, herbicidally or fertilizing bioactive material core, soluble in a given surrounding media, the core present in an amount at least sufficient for a total dosage during a treatment period; a first coating enveloping the bioactive material core comprising a polymer or a blend of polymers, said polymer or blend of polymers being swellable upon penetration by the surrounding media; and a second coating enveloping the first coating enveloped bioactive material core comprising a polymer or a blend of polymers; said polymer or blend of polymers being water-insoluble and forming a semi-permeable barrier permitting diffusion of the surrounding media into the first coating enveloped bioactive material core and also permitting the diffusion of the surrounding media dissolved bioactive material into the surrounding media. The first coating can further comprise a plasticizing agent. Examples of suitable first coating polymers are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol or mixtures thereof Examples of suitable second coating polymers are ethyl cellulose alone or in combination with hydroxypropyl cellulose or methyl cellulose.
Similar internally swellable microcapsule compositions are disclosed in the following patents:
U.S. Pat. No. 4,423,099 discloses non-uniform water-insoluble interpenetrating polymer blend compositions comprising a first permeable water swellable polymer substrate interpenetrated in a gradient substantially normal to the substrate surface by a second less permeable condensation polymer to form a diffusion rate controlling membrane therein. The resulting polymer blend is such that the concentration of the condensation polymer increases from 0% at the inner surface of the water swellable polymer to about 100% at the outer surface of the water swellable polymer.
U.S. Pat. No. 4,177,056 discloses a controlled, sustained release composition comprising a pharmaceutically, insecticidally or herbicidally effective agent and a water-insoluble hydrophilic gel comprising: (A) about 30 to about 90% of a hydrophilic (a) polymer of identical or different water-soluble mono-olefinic monomers, or (b) copolymer of the water-soluble monomers with 1 to 70% of water-insoluble, identical or different mono-olefinic monomers, which polymer or copolymer is cross linked with (B) about 10 to about 70% of a terminal diolefinac hydrophobic macromer having a molecular weight from about 400 to about 8000.
U.S. Pat. No. 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule containing film-coated spheroids, comprising propranolol or a pharmaceutically acceptable salt thereof, in admixture with a non-water swellable microcrystalline cellulose, with the spheroids having a film coat comprising ethylcellulose optionally together with hydroxypropyl methylcellulose and/or a plasticizer.
The food, nutriceutical, cosmetic and agricultural industry have benefited from the use of microcapsules prepared from encapsulating core materials in either hydrophilic or hydrophobic polymeric materials. These microcapsules have been prepared from molten mixtures which are both cooled and granulated or spray chilled thereby congealing the molten polymer about the core materials to form capsules or prills.
U.S. Pat. No. 5,599,583 discloses the encapsulation of an agriculturally effective active ingredient by mixing until homogeneous the ingredient with a water-free molten film-forming water soluble polymer binder, cooling the mixture and spraying the cooled mixture into a congealing zone to form particles.
U.S. Pat. No. 5,631,013 discloses encapsulated alkali metal bicarbonate crystallites coated with hydrophilic or water insoluble polymers, and specifically describes the fluicized bed coating of sodium bicarbonate using solutions of hydrophilic polymers.
U.S. Pat. No. 3,080,293 discloses the preparation of niacinamide beadlets by admixing melted stearic acid with niacinamide powder passed through a centrifugal atomizer and spray chilled, dried and dusted with silicic acid.
U.S. Pat. No. 4,022,917 describes a batter that is made with particles of an alkaline leavening agent encapsulated in a water-insoluble coating that is added to the batter. The alkaline leavening agent is dispersed in the batter at a cooking temperature and is released at a temperature of at least about 60 degrees C.
The use of fats as a retention media for volatiles is disclosed in U.S. Pat. No. 3,949,094, wherein volatile flavorings, seasonings, colorants, flavor enhancers and the like are blended with lipoid material under super atmospheric conditions for subsequent handling or conversion into particulates by a spray chilling process. The '094 patent method and other similar spray-drying methods result in microcapsules of inferior quality. In essence, the “sealing” effect of core materials within fats by prior art methods is often insufficient resulting in unwanted core oxidation, reduction or volatilization, particularly when the capsules are exposed to environmental storage conditions or mechanical shear during subsequent processing.
More recent methods of microencapsulation are reported in U.S. Pat. No. 5,209,879 which discloses the use of a pressure-pulse, abrupt pressure change or shock wave (hereinafter “pressure-force”) to accelerate the conversion of polymorphic waxes to the more stable beta crystalline state and the use of such beta waxes as shell materials in the preparation of microcapsules for environmentally sensitive materials. WO9115198, derived from a US application filed on the same day as the application that issued as the above-mentioned '879 patent, discloses the possible preparation of a beta crystalline wax encapsulate by the pre-mixing of the core material with the liquid wax prior to the application of the pressure-force. The patentee notes however that this procedure results in frequent machine jamming. The pressure pulse technology has also been described as applicable to the encapsulation of fluids such as liquids in U.S. Pat. No. 5,460,756 that discloses the encapsulation of liquids within the pressure force-treated polymorphic wax by mixing the liquid core with the molten wax either before or after subjecting the mixture to pressure force. In all the pressure force methods, the molten mixture is cooled and granulated to form the stabilized beta wax encapsulated microcapsules.
It is an object of this invention to provide long term storage-stable microcapsule compositions that possess the capacity to release core material at a constant rate in an aqueous environment and/or release the core as a function of a defined temperature range. These and other objects will become apparent in the following description of the invention.